title: A regenerative approach to the treatment of multiple sclerosis.
abstract: Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Vishal A
authors.initials: VA
authors.lastname: Deshmukh
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Virginie
authors.initials: V
authors.lastname: Tardif
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Chelsea C
authors.initials: CC
authors.lastname: Green
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Bilal
authors.initials: B
authors.lastname: Kerman
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Krishnan
authors.initials: K
authors.lastname: Padmanabhan
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Swoboda
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Insha
authors.initials: I
authors.lastname: Ahmad
authors.affiliation: Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi- 7, Kita-ku, Sapporo 060-0815, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Argyrios N
authors.initials: AN
authors.lastname: Theofilopoulos
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lawson
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA.|The California Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA.|The California Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Luke L
authors.initials: LL
authors.lastname: Lairson
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use; D001590:Benztropine / Q000494:pharmacology / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D018920:Coculture Techniques; D003471:Cuprizone / Q000494:pharmacology / Q000627:therapeutic use; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D000068876:Fingolimod Hydrochloride; D007107:Immune System / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology; D018991:Myelin Proteolipid Protein / Q000494:pharmacology; D009186:Myelin Sheath / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009900:Optic Nerve / Q000166:cytology; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012008:Recurrence; D012038:Regeneration / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects
chemical_list: D000978:Antiparkinson Agents; D018991:Myelin Proteolipid Protein; D011409:Propylene Glycols; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D001590:Benztropine; D003471:Cuprizone; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine